Dementia is a debilitating and life-altering disease that leads to memory impairment and decline of normal executive functioning. While the causes of dementia are numerous, the leading causes among patients 60 years and older are Alzheimer's disease (AD) and dementia with Lewy bodies. AD represents a significant public health concern because of its associated personal, social and economic burdens. Previously, diagnosis of AD required histopathological confirmation based on lesions in brain cortical structures, which lesions are characterized by an extracellular senile plaque and an intracellular neurofibrillary tangle. Such histopathological confirmation poses unique challenges due to the sensitivity of brain tissue to biopsy. As such, better diagnostic tools for identifying AD are desirable.
GMF-B (glia maturation factor beta) belongs to the actin-binding proteins (ADF) structural family. GMF-B is a 141 amino acid protein isolated from brain and identified as a growth and differentiation factor, acting on neuorons as well as glia. GMF-B is expressed predominantly in the brain, especially by astrocytes an some neuronal cells. GMF-B is located on chromosome 14q22.2. GMF-B has been sequenced and otherwise characterized under UniProt P60983, NCBI Gene 2764; NCBI RefSeq NP—004115.1; NCBI RefSeq NM—004124.2, NP—006187; NCBI UniGene 5093; and NCBI Accession AK130439, AAA91317. Homologues of GMF-B are also known, including, but not limited to, homologues of GMF-B in the mouse (see NCBI UniGene 23983; UniProt P60335; and NCBI RefSeq NM—011865, NP—035995), dog, and rat, and GMF-B is highly conserved.
GMF-B is an acidic (pI=5.2) protein of 17 kDa. The unprocessed bovine and human GMF-B having a length of 142 amino acids, including the first methionine, and contain three cysteine residues (Lim et al., FASEB J 4:3360-3363, 1990; Kaplan et al., Journal of Neurochemistry 57(2):483-490, 1991). See SEQ ID NO: 9. Two of the cysteines (position 87 and 96 of unprocessed GMF-B (SEQ ID NO: 9); position 87 and 96 of processed GMF-B (SEQ ID NO: 11); and position 86 and 95 of Met processed GMF-B (SEQ ID NO: 10 or 12)) form a disulfide bond that is reported as essential for bioactivity. GMF-B may also be phosphorylated at residue 84 of SEQ ID NOs: 9 or 11 or residue 83 of SEQ ID NO: 10 or 12. GMF-B has a blocked amino terminus (N-Acetyl-serine). Cell surface expression of GMF-B has been shown, and it was documented that GMF-B is not secreted (Lim et al., FASEB J, 4:3360-3363, 1990). GMF-B does not display any significant homology to other sequenced proteins (Lim and Zaheer, 1991). For a related highly homologous factor see also: GMF-gamma.
GMF-B is reported to play a role in the differentiation, maintenance and regeneration of the nervous system. GMF-B also has been reported to support the progression of certain auto-immune diseases, possibly through its ability to induce the production and secretion of various pro-inflammatory cytokines e.g., interleukin-1beta and MHC class II. Moreover, the addition of a soluble recombinant GMF-B to neoplastic cells in culture resulted in a reported inhibition of proliferation and the arresting of cells in the G0/G1 phase (Lim et al., Cell Regulation 1:741-746, 1990) (Lim et al., J Biol. Chem. 271:22953-56, 1996). Furthermore, GMF-B was reported to inhibit the proliferation of tumors derived from neuronal cell types. Unlimited growth of gliomas has been reported to be due to a defect in the transport of GMF-B from the cytosol to the cell surface. A reversible inhibition of a number of neuronal and non-neuronal neoplastic cells by GMF-B is also observed (Lim et al, 1990).
Many reports also suggest that GMF-B plays a role in neuroprotection against adverse environmental conditions (Zaheer, et al., Neurochem. Res. 26: 1293-1299, 2001; Lim, et al., Neurochem. Res. 23: 1445-1451, 1998; Lim, et al., J. Neurochem. 74: 596-602, 2000; Zaheer, et al., Neurosci. Lett. 265: 203-206, 1999; Pantazis et al., Brain Res. 865: 59-76, 2000). For example, the application of GMF-B to an injured brain promotes the appearance of large neurons in the cerebral cortex (Kaplan, et al., J. Neuorchem. 57: 483-490, 1991); Lim, et al., Proc. Natl. Acad. Sci. USA 86: 3901-3905, 1989; Lim, et al., Methods Enzymol. 147: 225-235, 1987; Lim, et al., Brain Res. 430: 93-100, 1987; Lim, et al., Brain Res. 468: 277-284, 1988; Lim, et al., Brain Res. 504: 154-158, 1989; Bosch, et al., J. Neurosci. 9: 3690-3698, 1989; Nieto-Sampedro, et al., Neurosci. Lett. 86:361-365, 1988; Lim, et al., Brain Res. 430: 49-57, 1987; Ryken, et al., Int. J. Dev. Neurosci. 5: 215-225, 1987; Lim, et al., Cancer Res. 46: 5241-5247, 1986; Yamazaki, et al., Histopathology 47: 292-302, 2005). By contrast, overexpression of GMF-B in astrocytes leads to the destruction of primary oligodendrocytes, implicating a GMF-B-related neural cytotoxicity (Menon, et al., Neurosci. Res. 58: 156-163, 2007); Zaheer, et al., J. Neurochem. 101: 364-376, 2007; Zaheer, et al., Neurochem. Res. 32: 39-47, 2007; Zaheer, et al., Brain Res. 1144: 239-247, 2007; Zaheer, et al., Neurochem. Res. 32: 2123-2131, 2007).
As such, it there is a need to further examine GMF-B expression in the brain and blood after neural degeneration, such as that caused by dementia, including Alzheimer's disease. For example, of great interest would be the development of additional diagnostic and therapeutic tools for disease states, including for example dementia, based upon GMF-B expression and the use of GMF-B antibodies.